Cardiopulmonary-renal complications are now the most common cause of mortality in sickle cell disease (SCD). Cardiovascular pathology is overshadowed by the effects of chronic anemia: presence of biventricular hypertrophy but normal ejection fractions. Left ventricular diastolic dysfunction and sudden unexplained deaths also occur commonly. Pulmonary artery hypertension (PAH) in SCD has been the focus of recent research and debate. Mildly elevated pulmonary arterial (PA) pressures, estimated by a tricuspid regurgitation jet velocity (TRV)>2.5m/s have been associated with high mortality in several studies. However, cardiac catheterization diagnosed PAH is only present in 25-33% of those with TRV>2.5m/s. Nevertheless, the number of adverse events in SCD patients with even very mild elevation in PA pressures is unexpectedly high and its mechanism/s is unknown. High TRV strongly associates with renal pathology in SCD. Based upon our preliminary data, we hypothesize that reactive oxygen species (ROS) and angiotensin 11 (AT)-AT1 receptor (AT1R) is activated in SCD to generate TGF1, a profibrotic thrombo-lnflammatory cytokine that mediates SCD cardio-renal disease and sudden death, by causing a profibrotic state and a unique restrictive cardiomyopathy (RCM) with secondary PAH. We will (Aim 1) test whether the' increased ROS in SCD is derived via RAS-mediated G-protein signaling to worsen oxidative membrane damage and hemolysis using pharmacological, or genetic approaches and study the effects of ROS on cardio-renal pathologies; (Aim 2) examine the relative contribution of cardiac or renal AT1R signaling or TGF1 production using mice deficient in AT1R or TGFbeta1 specifically in cardiac or renal tissues. We will also study the effects of TGF1 derived from platelets, the largest source of circulating TGF1 by using mice deficient in TGP1 specifically in platelets and study the effect on cardio-renal pathology; and (Aim 3) explore novel cardiac MR modalities to detect the unique restrictive cardiomyopathy and quantify diffuse myocardial fibrosis in patients with SCD with and without high TRV. The same novel CMR imaging will also be done in mice, where imaging can be correlated with anatomical and histopathological analysis. The diverse team of multidisciplinary investigators in hematology, cardiology and radiology, pharmacological and genetic approaches, and parallel human studies will allow a multifaceted analysis of the cardio-renal pathologies in SCD, to allow rapid translation of research discoveries into therapeutic targets and a future phase ll/lll trials.